Alzheimer's disease (AD) is known to affect particular molecules, cells, and brain regions, often referred to as 'selective vulnerability'. Previous investigations of regional vulnerability have found classical pathologic changes (such as neurofibrillary tangles) as well as gray matter loss measured by MR imaging primarily in the medial temporal lobe in early AD. In contrast, many functional brain imaging studies of early AD have demonstrated severe metabolic reduction in the posterior cingulate and association cortices before the onset of dementia. These independent observations raise an interesting question regarding regional vulnerability of the brain in very early AD. This discordance may be attributed in part to differences in the nature AND limitations of investigational methods. For example, precise quantitative assessment of mild neurodegeneration in a large area of cortices is difficult by conventional structural imaging and histopathologic examinations. In addition, previous structural studies have focused on a limited number of a priori selected regions, such as medial temporal lobe structures, for the analysis. We investigated regional gray matter loss in the entire brain using MR imaging combined with a novel gray matter density mapping technique and found significant and region-specific gray matter loss not only in the medial temporal lobe, but also in the posterior cingulate and lateral association cortices in mild AD. In this proposal, we would like to extend our investigations to preclinical stage of AD and examine if neurodegeneration in the posterior cingulate and association cortices that are tightly interconnected with each other and directly to the entorhinal cortex is a very early and consistent pathologic process that has been overlooked. One important emphasis in our proposal is to examine vulnerability of interconnected cerebral regions, instead of a single discrete focus, to better understand regional vulnerability of very early AD. Precise delineation of regional selective vulnerability in very early disease is not only critical for better understanding of the macroscopic disease process, but also provides a basis for further regional histopathologic and molecular investigations. If very early involvement of the posterior cingulate and association cortices are found consistently, these findings will provide better markers for early detection of the disease and monitoring of disease progression.